BDNF promoter methylation and genetic variation in late-life depression.

V Januar,R Saffery,M-L Ancelin,K Ritchie,J Ryan

doi:10.1038/tp.2015.114

Abstract

The regulation of the brain-derived neurotrophic factor (BDNF) is important for depression pathophysiology and epigenetic regulation of the BDNF gene may be involved. This study investigated whether BDNF methylation is a marker of depression. One thousand and twenty-four participants were recruited as part of a longitudinal study of psychiatric disorders in general population elderly (age⩾65). Clinical levels of depression were assessed using the Mini International Neuropsychiatric Interview for the diagnosis of major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorder IV criteria, and the Centre for Epidemiologic Studies Depression Scale (CES-D) for assessment of moderate to severe depressive symptoms. Buccal DNA methylation at the two most widely studied BDNF promoters, I and IV, was investigated using the Sequenom MassARRAY platform that allows high-throughput investigation of methylation at individual CpG sites within defined genomic regions. In multivariate linear regression analyses adjusted for a range of participant characteristics including antidepressant use, depression at baseline, as well as chronic late-life depression over the 12-year follow-up, were associated with overall higher BDNF methylation levels, with two sites showing significant associations (promoter I, Δ mean=0.4%, P=0.0002; promoter IV, Δ mean=5.4%, P=0.021). Three single-nucleotide polymorphisms (rs6265, rs7103411 and rs908867) were also found to modify the association between depression and promoter I methylation. As one of the largest epigenetic studies of depression, and the first investigating BDNF methylation in buccal tissue, our findings highlight the potential for buccal BDNF methylation to be a biomarker of depression.

Highlights

As one of the most common psychiatric disorders, depression is a major public health problem, accounting for 40.5% of disabilityadjusted life years worldwide.[1]
Several single-nucleotide polymorphisms (SNPs) in the brain-derived neurotrophic factor (BDNF) gene have been associated with the risk of major depression[9] and the regulation of serotonin.[10]
We investigated BDNF methylation levels at two CpG islands within promoters I and IV, using DNA derived from buccal tissue, and determined whether there was an association with clinical levels of depression at baseline, as well as chronic depression

Summary

Introduction

As one of the most common psychiatric disorders, depression is a major public health problem, accounting for 40.5% of disabilityadjusted life years worldwide.[1]. Few genetic variants have been identified.[5] Among the potential candidates is the gene coding for brain-derived neurotrophic factor (BDNF), which promotes the proliferation, differentiation and survival of neurons and is crucial for neural plasticity and cognitive function.[6] Lower circulating levels of BDNF have been observed in depressed patients compared with non-depressed individuals.[7] Effective antidepressant treatments appear to increase circulating BDNF levels, and higher plasma BDNF may predict better antidepressant response.[8] Several single-nucleotide polymorphisms (SNPs) in the BDNF gene have been associated with the risk of major depression[9] and the regulation of serotonin.[10]

Results

Discussion

Conclusion